Synthesis, Cytotoxicity, DNA Interaction, and Topoisomerase II Inhibition Properties of Novel Indeno[2,1-c]quinolin-7-one and Indeno[1,2-c]isoquinolin-5,11-dione Derivatives

• Published in: Journal of medicinal chemistry 2008-06, Vol.51 (12), p.3617-3629
• Main Authors: Ryckebusch, Adina, Garcin, Deborah, Lansiaux, Amélie, Goossens, Jean-François, Baldeyrou, Brigitte, Houssin, Raymond, Bailly, Christian, Hénichart, Jean-Pierre
• Format: Article
• Language: English
• Subjects: Antineoplastic agents; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Biological and medical sciences; Cell Line, Tumor; DNA - chemistry; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Fluorescence; General aspects; Humans; Indenes - chemical synthesis; Indenes - chemistry; Indenes - pharmacology; Isoquinolines - chemical synthesis; Isoquinolines - chemistry; Isoquinolines - pharmacology; Medical sciences; Mitoxantrone - pharmacology; Nucleic Acid Denaturation; Pharmacology. Drug treatments; Quinolines - chemical synthesis; Quinolines - chemistry; Quinolines - pharmacology; Structure-Activity Relationship; Topoisomerase II Inhibitors
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm800017u

Indeno[2,1-c]quinolin-7-ones and 6H-indeno[1,2-c]isoquinolin-5,11-diones, bearing two cationic aminoalkyl side chains, were synthesized and evaluated for DNA interaction, topoisomerases inhibition, and cytotoxicity against human cancer cell lines. They displayed strong interaction with DNA and one indeno[1,2-c]isoquinolin-5,11-dione bearing side chains at N-6 and C-8 positions (6a) was a potent human topoisomerase II inhibitor with high cytotoxicity toward HL60 cells. An increased topoisomerase II inhibition is found with (a) a cationic aminoalkyl side chain at the C-8 rather than at the C-9 position, (b) a dimethylaminoethoxy side chain at the C-8 position introduced on the N-6 monosubstituted derivative, going with suppression of topoisomerase I poisoning, and (c) a dimethylaminoethyl rather than a dimethylaminopropyl side chain at the N-6 position. The cytotoxicity was only partially reduced when using the topoisomerase II-mutated mitoxantrone-resistant HL60/MX2 cell line, suggesting that additional targets are involved in their mechanism of action. These indeno[1,2-c]isoquinolin-5,11-dione derivatives represent new DNA−topoisomerase II interfering anticancer molecules.